61:
37:
140:
HLS presents itself as various, lethal developmental abnormalities, which often result in either premature stillbirth or death shortly after birth. Rare cases of children born with HLS surviving for several months have been noted. A characteristic abnormality of HLS is an absence of brain tissue and
401:
No cure or treatment option for individuals with HLS currently exist. Due to the severity of the foetal defects and the poor prognosis for those with HLS, the pregnancy is often terminated. Certain prevention can only be achieved by avoiding conception if genetic testing indicates both prospective
544:
Putoux A, Thomas S, Coene K, Davis E, Alanay Y, Ogur G, Uz E, Buzas D, Gomes C, Patrier S, Bennett C, Elkhartoufi N, Frison M, Rigonnot L, Joyé N, Pruvost S, Utine G, Boduroglu K, Nitschke P, Fertitta L, Thauvin-Robinet C, Munnich A, Cormier-Daire V, Hennekam R, Colin E, Akarsu N, Bole-Feysot C,
356:
result in a different genomic sequence disruption to the missense mutation of HLS, and phenotypically present as JS. The ‘molar tooth sign’ of the brain, an anomaly in which cerebellar volume is reduced but cerebellar shape is retained, resembles the molar tooth and is used to identify JS. JS
104:
are microscopic projections that allow sensory input and signalling output within cells, as well as cell motility. Dysfunction results in a range of abnormalities that are often the result of improper cell signalling. A variant form, HLS2, with additional mutations to the
275:. As cilia are located in almost all cells throughout the body, cilial dysfunction causes developmental defects in a range of organs and thus the phenotype of HLS can vary greatly, though brain malformation and polydactyly are most commonly observed.
1000:
214:, with incidences more common in Finland than the rest of the world; roughly 1 in 20,000 developing foetuses are affected in Finland. Rare cases in other regions have also been documented, often with less severe
157:) are common during pregnancy with a HLS-affected foetus, with cases of up to 8 litres cited compared to the normal 1 litre. Less common symptoms such as abnormally small eyes and a broad nose are also possible.
960:
311:
and adjoining to the plasma membrane, lack proper development. As these structures form the cilial gate, improper development results in a loss of selectivity for protein entry into the ciliary compartment.
210:
syndrome; development is only possible if both parents carry the defective gene, and in that instance, the risk of the foetus developing the syndrome is 25%. HLS is a member of the
452:
Oka M, Shimojima K, Yamamoto T, Hanaoka Y, Sato S, Yasuhara T, Yoshinaga H, Kobayashi K (June 2016). "A novel HYLS1 homozygous mutation in living siblings with
Joubert syndrome".
545:
Cagnard N, Schmitt A, Goudin N, Lyonnet S, Encha-Razavi F, Siffroi J, Winey M, Katsanis N, Gonzales M, Vekemans M, Beales P, Attié-Bitach T (June 2011).
237:, genes in other species with common ancestral heritage, have been examined to explain the pathophysiology of HLS; a similar gene within the roundworm,
222:
variability across countries, allowing survival of affected offspring for up to several months. Individuals of
Finnish descent are advised to undergo
145:) as a result of abnormal development of the central nervous system. Other common defects include incomplete lung development, heart defects, a
243:, is responsible for the formation of cilia. Current hypotheses place a dysfunction of cilia as the main cause of HLS defects arising from the
307:
gene to correctly target centrioles to the plasma membrane. Specifically, transition fibres within the transition zone, at the base of the
386:
1012:
128:). HLS can be distinguished from Meckel syndrome by analysing kidney function, which is dysfunctional in Meckel syndrome as a result of
749:"Unraveling the disease pathogenesis behind lethal Hydrolethalus syndrome revealed multiple changes in molecular and cellular level"
389:, which present with similar physiological defects. HLS can be detected at the end of the first trimester, approximately 13 weeks
381:
and an abnormal structure of the brain. Precise examination via ultrasound or at birth is necessary to rule out Meckel syndrome,
805:
Mee L, Honkala H, Kopra O, Vesa J, Finnilä S, Visapää I, Sang T, Jackson G, Salonen R, Kestilä M, Peltonen L (April 2005).
1101:
1096:
340:
encodes a structural factor vital to cilial transport, and is also implicated in other developmental disorders, such as
747:
Honkala H, Lahtela J, Fox H, Gentile M, Pakkasjärvi N, Salonen R, Wartiovaara K, Jauhiainen M, Kestilä M (April 2009).
900:
Wei Q, Zhang Y, Schouteden, C, Zhang, Y, Zhang, Q, Dong, J, Wonesch, V, Ling, K, Dammermann, A, Hu, J (August 2016).
263:
and forms small clusters, suggesting that the mutant gene disrupts cellular localisation. The protein encoded by the
1023:
211:
433:
239:
121:
1074:
288:
284:
120:. Like HLS, Meckel syndrome presents with severe physiological abnormalities, namely disruptions to the
100:
mutations. The gene encoding HYLS1 is responsible for proper cilial development within the human body.
913:
851:
Dammermann A, Pemble H, Mitchell B, McLeod I, Yate J, Kintner C, Desai A, Oegema K (September 2009).
206:; proper functioning of exons 1-5 ensures regulation and expression of the entire protein. HLS is an
60:
207:
361:
mutation is the sole cause of HLS, but is also present in the HLS2 variant form with the mutated
324:
have also been noted in patients that present a similar phenotype to HLS and the characteristic
1034:
939:
882:
828:
780:
690:
630:
576:
521:
469:
287:
are known to increase the likelihood of HLS development or progression; HLS is caused only by
171:
82:
49:
853:"The Hydrolethalus syndrome protein HYLS-1 links core centriole structure to cilia formation"
929:
921:
872:
864:
818:
770:
760:
680:
672:
620:
612:
566:
558:
511:
503:
461:
348:
are no longer explicitly connected to HLS in humans. Homozygous mutations removing the stop
341:
113:
also ensures correct cilia formation and function, specifically cilia stability and length.
78:
54:
116:
Hydrolethalus syndrome (HLS) was first mistakenly identified in
Finland, during a study on
300:
223:
117:
36:
917:
153:, polydactyly, and an abnormally small jaw. Stillbirth and an excess of amniotic fluid (
934:
901:
877:
852:
775:
748:
685:
660:
625:
600:
571:
546:
516:
491:
154:
1090:
195:
179:
142:
902:"The hydrolethalus syndrome protein HYLS-1 regulates formation of the ciliary gate"
378:
260:
150:
86:
1028:
125:
1039:
807:"Hydrolethalus syndrome is caused by a missense mutation in a novel gene HYLS1"
303:
of HLS is abnormal cilia development arising from the inability of the mutated
616:
507:
382:
374:
329:
272:
268:
215:
183:
90:
1045:
390:
256:
248:
234:
233:
gene was unknown, and similar genes within humans have not been identified.
202:(D211G) in the polypeptide chain. Exon 6 is the only protein coding exon in
146:
943:
886:
832:
784:
634:
580:
525:
473:
765:
694:
676:
1069:
823:
806:
729:
Honkala H (March 2009). "The molecular basis of hydrolethalus syndrome".
992:
925:
868:
308:
199:
465:
271:
to the plasma membrane, disrupting ciliary function, which results in
1004:
547:"KIF7 mutations cause fetal hydrolethalus and acrocallosal syndromes"
219:
44:
Hydrolethalus syndrome is inherited in an autosomal recessive manner
562:
255:
have been clearly observed; the wild type form is localised to the
1050:
415:
349:
101:
97:
373:
HLS can be readily diagnosed during pregnancy through the use of
1017:
191:
129:
141:
midline structures, with the presence of excess brain fluid (
357:
presents with mutations in more than 30 genes, whilst the
267:
mutant form is unable to carry out essential targeting of
178:
982:
1060:
986:
48:
26:
21:
492:"Ciliopathies: an expanding disease spectrum"
8:
259:, while the mutant form is localised to the
955:
953:
124:and the presence of extra fingers or toes (
983:
601:"Gated entry into the ciliary compartment"
59:
35:
18:
933:
876:
822:
774:
764:
684:
624:
570:
515:
336:gene causes a variant form of HLS, HLS2.
247:mutation in humans. Differences between
654:
652:
650:
648:
646:
644:
426:
846:
844:
842:
800:
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441:
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714:
712:
710:
708:
706:
704:
402:parents as carriers of the defective
7:
659:Salonen R, Herva R (December 1990).
605:Cellular and Molecular Life Sciences
229:Prior to the discovery of HLS, the
599:Takao D, Verhey K (January 2016).
316:Variations and related pathologies
14:
344:(JS). Additionally, mutations in
490:Waters A, Beales P (July 2011).
434:E-Notes: Hydrolethalus Syndrome
226:before attempting to conceive.
194:6 involves the replacement of
182:; a single base change to the
1:
30:Salonen-Herva-Norio syndrome
665:Journal of Medical Genetics
170:HLS is caused by a genetic
1118:
387:Smith–Lemli–Opitz syndrome
377:, which will often reveal
961:"Orphanet: Hydrolethalus"
617:10.1007/s00018-015-2058-0
508:10.1007/s00467-010-1731-7
43:
34:
811:Human Molecular Genetics
661:"Hydrolethalus syndrome"
212:Finnish disease heritage
857:Genes & Development
328:A to G transformation;
96:HLS is associated with
240:Caenorhabditis elegans
122:central nervous system
109:gene, is less common.
71:Hydrolethalus syndrome
22:Hydrolethalus syndrome
906:Nature Communications
766:10.1186/1755-8417-2-2
677:10.1136/jmg.27.12.756
289:genetic abnormalities
285:environmental factors
81:that causes improper
1102:Syndromes in females
1097:Congenital disorders
496:Pediatric Nephrology
89:and, most commonly,
926:10.1038/ncomms12437
918:2016NatCo...712437W
869:10.1101/gad.1810409
208:autosomal recessive
1061:External resources
824:10.1093/hmg/ddi157
136:Signs and symptoms
1084:
1083:
466:10.1111/cge.12752
454:Clinical Genetics
172:missense mutation
83:fetal development
68:
67:
16:Medical condition
1109:
984:
972:
971:
969:
968:
957:
948:
947:
937:
912:(12437): 12437.
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880:
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826:
802:
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478:
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436:
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342:Joubert syndrome
332:deletion of the
79:genetic disorder
64:
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55:Medical genetics
39:
19:
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1111:
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995:
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976:
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964:
959:
958:
951:
899:
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894:
863:(17): 2046–59.
850:
849:
840:
817:(11): 1475–88.
804:
803:
792:
746:
745:
738:
728:
727:
702:
658:
657:
642:
598:
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551:Nature Genetics
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371:
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301:pathophysiology
297:
295:Pathophysiology
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224:genetic testing
218:as a result of
168:
163:
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118:Meckel syndrome
85:, resulting in
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17:
12:
11:
5:
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987:Classification
980:
979:External links
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974:
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949:
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838:
790:
736:
700:
671:(12): 756–59.
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563:10.1038/ng.826
531:
502:(7): 1039–56.
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155:polyhydramnios
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611:(1): 119–27.
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460:(6): 739–43.
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366:
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352:in exon 4 of
351:
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320:Mutations in
315:
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279:Environmental
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196:aspartic acid
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186:sequence for
185:
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180:chromosome 11
177:
173:
165:
160:
158:
156:
152:
148:
144:
143:hydrocephalus
135:
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87:birth defects
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56:
53:
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38:
33:
29:
25:
20:
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999:
965:. Retrieved
963:. 2017-09-10
909:
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731:ResearchGate
730:
668:
664:
608:
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557:(6): 601–6.
554:
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379:hydrocephaly
372:
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187:
175:
169:
139:
115:
110:
106:
95:
77:) is a rare
74:
70:
69:
251:and mutant
132:formation.
126:polydactyly
27:Other names
1091:Categories
1035:DiseasesDB
967:2017-09-10
421:References
383:Trisomy 13
375:ultrasound
330:homozygous
273:ciliopathy
269:centrioles
216:phenotypes
184:amino acid
91:stillbirth
1051:721232000
1046:SNOMED CT
733:: 756–59.
397:Treatment
391:gestation
369:Diagnosis
257:cytoplasm
249:wild type
235:Orthologs
198:211 with
147:cleft lip
50:Specialty
1070:Orphanet
944:27534274
887:19656802
833:15843405
785:19400947
759:(2): 2.
635:26472341
581:21552264
526:21210154
474:26830932
410:See also
1029:C536079
1008:: Q87.8
935:4992140
914:Bibcode
878:2751977
776:2686686
695:2074561
686:1017280
626:4959937
572:3674836
517:3098370
309:axoneme
261:nucleus
200:glycine
174:of the
166:Genetic
1018:236680
942:
932:
885:
875:
831:
783:
773:
693:
683:
633:
623:
579:
569:
524:
514:
472:
406:gene.
365:gene.
220:allele
151:palate
57:
1040:34380
416:HYLS1
404:HYLS1
385:, or
359:HYLS1
354:HYLS1
350:codon
346:HYLS1
326:HYLS1
305:HYLS1
265:HYLS1
253:HYLS1
245:HYLS1
231:HYLS1
204:HYLS1
188:HYLS1
176:HYLS1
161:Cause
102:Cilia
98:HYLS1
1075:2189
1024:MeSH
1013:OMIM
940:PMID
883:PMID
829:PMID
781:PMID
691:PMID
631:PMID
577:PMID
522:PMID
470:PMID
363:KIF7
338:KIF7
334:KIF7
322:KIF7
299:The
192:exon
130:cyst
111:KIF7
107:KIF7
1001:ICD
930:PMC
922:doi
873:PMC
865:doi
819:doi
771:PMC
761:doi
681:PMC
673:doi
621:PMC
613:doi
567:PMC
559:doi
512:PMC
504:doi
462:doi
190:in
149:or
75:HLS
1093::
1073::
1049::
1038::
1027::
1016::
1005:10
952:^
938:.
928:.
920:.
908:.
904:.
881:.
871:.
861:23
859:.
855:.
841:^
827:.
815:14
813:.
809:.
793:^
779:.
769:.
755:.
751:.
739:^
703:^
689:.
679:.
669:27
667:.
663:.
643:^
629:.
619:.
609:73
607:.
603:.
589:^
575:.
565:.
555:43
553:.
549:.
534:^
520:.
510:.
500:26
498:.
494:.
482:^
468:.
458:89
456:.
440:^
393:.
291:.
93:.
1003:-
993:D
970:.
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924::
916::
910:7
889:.
867::
835:.
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763::
757:2
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675::
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615::
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561::
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506::
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464::
414:•
73:(
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